Completion of phenotyping and screening pulmonary function studies in the over 500 MRFIT subjects is to be completed during this third year. We plan to do statistical analysis of the data, specifically of the identified 36 MZ's to be matched with MM's for age, sex and smoking history from our four random populations of over 1,000 subjects. In addition, 26 MZ's from the random population and over 60 MZ's, 27 ZZ's and 22 SS and SZ's from the pulmonary lab and kindred populations are available for longitudinal studies to determine which of the non-invasive pulmonary studies are most useful in defining the clinical and physiologic course of emphysema. Over 200 He-O2 flow-volume studies are also to be analyzed from these populations. The biochemical basis of a) microheterogenity within each phenotype and b) the AAT deficiency state in ZZ individuals remains largely undefined. We have isolated both variants in pure form. In the coming year these proteins will be compared by immunological methods. In addition, chemical modifications of sugar residues will be carried out in an attempt to prolong the circulating half-life of AAT. This would increase the feasibility of replacement therapy. Isoelectric focusing will be used to separate the individual bands within each phenotype for more detailed biochemical analysis of peptide and sugar differences. Finally, using immunological and biological assays, as well as isoelectric focusing, SDS-gel electrophoresis and gel filtration, we propose to study the relevance of protease-inhibitor complexes in several human diseases including myocardial infarction, acute respiratory disease and pneumonia, and acute pancreatitis.